Cdk5‐mediated phosphorylation regulates phosphatidylinositol 4‐phosphate 5‐kinase type I γ 90 activity and cell invasion

Abstract

Phosphatidylinositol 4-phosphate 5-kinase type I γ (PIPKIγ90) regulates cell migration, invasion, and metastasis. However, it is unknown how cellular signals regulate those processes. Here, we show that cyclin-dependent kinase 5 (Cdk5), a protein kinase that regulates cell migration and invasion, phosphorylates PIPKIγ90 at S453, and that Cdk5-mediated PIPKIγ90 phosphorylation is essential for cell invasion. Moreover, Cdk5-mediated phosphorylation down-regulates the activity of PIPKIγ90 and the secretion of fibronectin, an extracellular matrix protein that regulates cell migration and invasion. Furthermore, inhibition of PIPKIγ activity with the chemical inhibitor UNC3230 suppresses fibronectin secretion in a dose-dependent manner, whereas depletion of Cdk5 enhances fibronectin secretion. With total internal reflection fluorescence microscopy, we found that secreted fibronectin appears as round dots, which colocalize with Tks5 and CD9 but not with Zyxin. These data suggest that Cdk5-mediated PIPKIγ90 phosphorylation regulates cell invasion by controlling PIPKIγ90 activity and fibronectin secretion.-Li, L., Kołodziej, T., Jafari, N., Chen, J., Zhu, H., Rajfur, Z., Huang, C. Cdk5-mediated phosphorylation regulates phosphatidylinositol 4-phosphate 5-kinase type I γ 90 activity and cell invasion.

PIPKIγ Regulates CCL2 Expression in Colorectal Cancer by Activating AKT-STAT3 Signaling

“…PIPKI γ was reported to regulate cell migration in multiple ways, such as through the EGF receptor (EGFR), upon Y639 phosphorylation by receptor tyrosine kinases (RTKs) [10, 11]. PIPKI γ could regulate neoplastic adhesion formation at the front edge through direct interaction with talin [12]. Additionally, PIPKI γ could bind to AP2, an adaptor of E-cadherin to clathrin, to reform E-cadherin-based intercellular adhesions and restore epithelial polarization [13].…”

Targeting the cyclin-dependent kinase 5 in metastatic melanoma

“…In addition to proliferation, several studies reported that CDK5 plays a role in regulating cancer cell motility. Depending on the study, CDK5 was shown to promote migration of cancer cells by phosphorylating actin-binding/regulatory proteins such as caldesmon, talin, or FAK, phosphatidylinositol 4-phosphate 5-kinase type I γ (PIPKIγ90), PIKE-A, a transcription factor USF2, or to indirectly activate small GTP-ases RalA and RalB (11,50,51,(58)(59)(60)(61)(62)(63). In contrast, other authors concluded that CDK5 serves to inhibit cancer cell migration and to suppress metastasis by phosphorylating a tumor-suppressor DLC1, a scaffold protein muskelin, a transmembrane glycoprotein PDPN, an epigenetic regulator EZH2, or a protein phosphatase PP2A (64)(65)(66)(67)(68).…”

Type Iγ phosphatidylinositol phosphate kinase promotes tumor growth by facilitating Warburg effect in colorectal cancer

“…Through generation of PI(4,5)P2, PIPKIγ is critically important in a variety of biological processes, such as focal adhesion assembly [6,30], ciliogenesis [31], centriole duplication [32], and leukocyte recruitment [33]. Notably, PIPKIγ is also widely implicated in many oncogenic phenotypes, such as cell proliferation [13,34], migration [35], invasion [12,28], and the epithelial to mesenchymal transition process [14]. The dysregulated expression pattern of PIPKIγ prompted us to investigate its neoplastic activities in colorectal cancer.…”

“…For example, talin recruits PIPKIγ to focal adhesions and the site-specific generation of PI (4,5)P2 enhances talin binding to β1-integrin [10,11]. Previously, many reports have revealed the important role of PIPKIγ in multiple oncogenic processes [12,13]. In breast cancer, PIPKIγ and talin couple phosphoinositide and adhesion signaling to control the epithelial to mesenchymal transition process [14].…”